1. Field of the Invention (Technical Field)
The present invention relates to peptide constructs for the treatment of sexual dysfunction in animals, including both male erectile dysfunction and female sexual dysfunction, including methods and formulations for the use and administration of the same.
2. Background Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Sexual dysfunction, including both penile erectile dysfunction or impotence and female sexual dysfunction, are common medical problems. Significant effort has been devoted over the last twenty or more years to develop methods, devices and compounds for treatment of sexual dysfunction. While more effort has been undertaken for treatment of penile erectile dysfunction, female sexual dysfunction is also an area to which significant research and effort has been devoted.
At present, one commonly used orally administered drug for treatment of sexual dysfunction in the male is Viagra(copyright), a brand of sildenafil, which is a phosphodiesterase 5 inhibitor, increasing the persistence of cyclic guanosine monophosphate and thereby enhancing erectile response. There are several other medical treatment alternatives currently available depending on the nature and cause of the impotence problem. Some men have abnormally low levels of the male hormone testosterone, and treatment with testosterone injections or pills may be beneficial. However, comparatively few impotent men have low testosterone levels. For many forms of erectile dysfunction, treatment may be undertaken with drugs injected directly into the penis, including drugs such as papaverin, prostaglandin E1, phenoxybenzamine or phentolamine. These all work primarily by dilating the arterial blood vessels and decreasing the venous drainage. Urethral inserts, such as with suppositories containing prostaglandin, may also be employed. In addition, a variety of mechanical aids are employed, including constriction devices and penile implants.
A variety of treatments have also been explored for female sexual dysfunction, including use of sildenafil, although the Food and Drug Administration has not specifically approved such use. Testosterone propionate has also been employed to increase or augment female libido.
Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. In one report, a cyclic xcex1-melanocyte-stimulating hormone (xe2x80x9cxcex1-MSHxe2x80x9d) analog, called Melanotan-II, was evaluated for erectogenic properties for treatment of men with psychogenic erectile dysfunction. Wessells H. et al., J Urology 160:389-393 (1998); see also U.S. Pat. No. 5,576,290, issued Nov. 19, 1996 to M. E. Hadley, entitled Compositions and Methods for the Diagnosis and Treatment of Psychogenic Erectile Dysfunction and U.S. Pat. No. 6,051,555, issued Apr. 18, 2000, also to M. E. Hadley, entitled Stimulating Sexual Response in Females. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Cyclic Analogs of Alpha-MSH Fragments, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Linear Analogs of Alpha-MSH Fragments. Melanotan-II is a peptide of the following formula: 
Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555. These peptides are described as being useful for both the diagnosis and treatment of psychogenic sexual dysfunction in males and females. These peptides are related to the structure of melanocortins.
In use of Melanotan-II, significant erectile responses were observed, with 8 of 10 treated men developing clinically apparent erections, and with a mean duration of tip rigidity greater than 80% for 38 minutes with Melanotan-II compared to 3.0 minutes with a placebo (p=0.0045). The drug was administered by subcutaneous abdominal wall injection, at doses ranging from 0.025 to 0.157 mg/kg body weight. Transient side effects were observed, including nausea, stretching and yawning, and decreased appetite.
The minimum peptide fragment of native xcex1-MSH needed for erectile response is the central tetrapeptide sequence, His6-Phe7-Arg8-Trp9 (SEQ ID NO:1). In general, all melanocortin peptides share the same active core sequence, His-Phe-Arg-Trp (SEQ ID NO:1), including melanotropin neuropeptides and adrenocorticotropin. Five distinct melanocortin receptor subtypes have been identified, called MC1-R through MC5-R, and of these MC3-R and MC4-R are believed to be expressed in the human brain. MC3-R has the highest expression in the arcuate nucleus of the hypothalamus, while MC4-R is more widely expressed in the thalamus, hypothalamus and hippocampus. A central nervous system mechanism for melanocortins in the induction of penile erection has been suggested by experiments demonstrating penile erection resulting from central intracerebroventricular administration of melanocortins in rats. While the mechanism of His-Phe-Arg-Trp (SEQ ID NO:1) induction of erectile response has not been fully elucidated, it has been hypothesized that it involves the central nervous system, and probably binding to MC3-R and/or MC4-R.
Other peptides and constructs have been proposed which are ligands that alter or regulate the activity of one or more melanocortin receptors. For example, International Patent Application No. PCT/US99/09216, entitled Isoquinoline Compound Melanocortin Receptor Ligands and Methods of Using Same, discloses two compounds that induce penile erections in rats. However, these compounds were administered by injection at doses of 1.8 mg/kg and 3.6 mg/kg, respectively, and at least one compound resulted in observable side effects, including yawning and stretching. Other melanocortin receptor-specific compounds with claimed application for treatment of sexual dysfunction are disclosed in International Patent Application No. PCT/US99/13252, entitled Spiropiperidine Derivatives as Melanocortin Receptor Agonists. 
Both cyclic and linear xcex1-MSH peptides have been studied; however, the peptides heretofore evaluated have had an amide or xe2x80x94NH2 group at the carboxyl terminus. See, for example, Wessells H. et al., J Urology, cited above; Haskell-Luevano C. et al., J Med Chem 40:2133-39 (1997); Schixc3x6th H. B. et al., Brit J Pharmacol 124:75-82 (1998); Schixc3x6th H. B. et al., Eur J Pharmacol 349:359-66 (1998); Hadley M. E. et al., Pigment Cell Res 9:213-34 (1996); Bednarek M. A. et al., Peptides 20:401-09 (1999); U.S. Pat. Nos. 6,054,556, 6,051,555 and 5,576,290; and, International Patent Applications PCT/US99/04111 and PCT/US98/03298. While significant research has been conducted in an effort to determine the optimal structure of xcex1-MSH peptides, including a variety of structure-function, agonist-antagonist, molecular modeling and pharmacophore studies, such studies have relied upon peptides with an art conventional xe2x80x94NH2 group at the carboxyl terminus. Further, it has long been believed that biologically active neuropeptides, including xcex1-MSH peptides, are amidated, with an xe2x80x94NH2 group at the carboxyl terminus, and that such amidation is required both for biological activity and stability. See, for example, Metabolism of Brain Peptides, Ed. G. O""Cuinn, CRC Press, New York, 1995, pp. 1-9 and 99-101.
The invention relates to a peptide that is a free acid or pharmaceutically acceptable salt thereof that includes the sequence His-Phe-Arg-Trp (SEQ ID NO:1), His-D-Phe-Arg-Trp, homologs of His-Phe-Arg-Trp (SEQ ID NO:1) or homologs of His-D-Phe-Arg-Trp. The peptide is preferably a cyclic peptide, and preferable has a terminal xe2x80x94OH at the carboxyl terminus. In a preferred embodiment, the peptide is Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH.
The invention also includes pharmaceutical compositions of matter, including a peptide of this invention and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a buffered aqueous carrier, and preferably a saline or citrate buffered carrier.
The peptide of this invention, and pharmaceutical compositions of this invention, may be used for stimulating sexual response in a mammal. The invention thus also includes a method for stimulating sexual response in a mammal, in which a pharmaceutically sufficient amount of a composition including His-Phe-Arg-Trp (SEQ ID NO:1), His-D-Phe-Arg-Trp, homologs of His-Phe-Arg-Trp (SEQ ID NO:1) or homologs of His-D-Phe-Arg-Trp is administered. In a preferred embodiment, the composition includes a peptide or pharmaceutically acceptable salt thereof of the formula Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH. The mammal may be male or female. In this method, the composition can also include a pharmaceutically acceptable carrier. The peptide or pharmaceutical composition may be administered by any means known in the art, including administration by injection, administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration and nasal administration. In a preferred embodiment, administration is by nasal administration of a metered amount of a formulation including an aqueous buffer, which buffer may be a saline or citrate buffer.
A primary object of the present invention is a melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction.
A second object is to provide a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of male sexual dysfunction, including erectile dysfunction.
Yet another object is to provide a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of female sexual dysfunction.
Yet another object is to provide a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction with substantially reduced incidence of undesirable side effects.
A primary advantage of the present invention is that it is efficacious at doses that do not cause deleterious side effects, such side effects including nausea, yawning, stretching, decreased appetite and other effects observed with Melanotan-II, or that causes decreased deleterious side effects as compared to Melanotan-II.
A second advantage of the present invention is that it provides compositions with a larger therapeutic window between desired therapeutic effects and the onset of undesired side effects than other melanocortin receptor-specific agents for the intended purpose.
Yet another advantage of the present invention is that it provides compositions with a greater safety margin between desired therapeutic effects and the onset of undesired side effects than other melanocortin receptor-specific agents for the intended purpose.
Yet another advantage of the present invention is that it provides a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction which is efficacious at significantly lower doses than Melanotan-II or other melanocortin receptor-specific agents.
Yet another advantage of the present invention is that it provides a peptide-based melanocortin receptor-specific pharmaceutical that is effective over a greater dose range, without deleterious side effects, than Melnotan-II or other melanocortin receptor-specific agents.
Yet another advantage of the present invention is that it provides a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction which is pharmaceutically active more rapidly following administration than Melanotan-II or other peptide-based melanocortin receptor-specific agents.
Yet another advantage of the present invention is that it provides a peptide-based melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction which, because of increased efficacy at low doses, may be administered by delivery systems other than art conventional intravenous, subcutaneous or intramuscular injection, including but not limited to nasal delivery systems and mucous membrane delivery systems.
Other objects, advantages and novel features, and further scope of applicability of the present invention will be set forth in part in the detailed description to follow, taken in conjunction with the accompanying drawings, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.